Novel process for preparing i-substituted benzodiazepine derivatives

ABSTRACT

NOVEL PROCESS FOR PREPARING 1-SUBSTITUTED BENZODIAZEPINE DERIVATIVES REPRESENTED BY THE FORMULA   1-(HO-CNH2N-),3-R2,5-R3,R1-2,3-DIHYDRO-1H-1,4-   BENZODIAZEPIN-2-ONE   WHEREIN R1 REPRESENTS HYDROGEN, HALOGEN, NITRO, C1-C4 ALKOXY, TRIFLUOROMETHYL OR CYANO; R2 REPRESENTS HYDROGEN, C1-C4 ALKYL, PHENYL OR ARALKYL; R3 REPRESENTS PYRIDL OR A GROUP OF THE FORMULA   R4,R5-PHENYL   (WHERE R4 AND R5 ARE INDEPENDENTLY HYDROGEN, HALOGEN, C1-C4 ALKYL, TRIFLUOROMETHYL OR CYANO); AND N REPRESENTS AN INTEGER OF 1 TO 4, WHICH COMPRISES REACTING AN AMINOPHENYLKETONE DERIVATIVE REPRESENTED BY THE FORMULA,   1-(HO-CNH2N-NH-),2-(R3-CO-),R1-BENZENE   WHEREIN R1, R3 AND N ARE THE SAME AS DEFINED ABOVE, WITH AN OXAZOLID-2,5-DIONE DERIVATIVE REPRESENTED BY THE FORMULA   4-R2-OXAZOLIDINE-2,5-DIONE   WHEREIN R2 IS THE SAME AS DEFINED ABOVE. THE 1-SUBSTITUTED BENZODIAZEPINE DERIVATIVES REPRESENTED BY THE FORMULA (I) HAVE PROMINENT EFFECTS AS TRANQUILIZER, MUSCLE RELAXANT, ANTISPASMODIC, ANTICONVULSANT AND HYPNOTIC.

United States Patent NOVEL PROCESS FOR PREPARING I-SUBSTI- TUTEDBENZODIAZEPINE DERIVATIVES Hisao Yamamoto, Nishinomiya, Shigeho Inaba,Takarazuka, Toshiyuki Hirohashi, Ashiya, Michihiro Yamamoto, Toyonaka,Kikuo Ishizumi and Mitsuhiro Akatsu, Ikeda, Isamu Maruyama, Miuoo,Yoshiharu Kume, Takarazuka, Kazuo Mori, Kobe, and Takahiro Izumi,Takarazuka, Japan, assignors to Sumitomo Chemical Company, Limited,Osaka, Japan No Drawing. Filed June 14, 1971, Ser. No. 153,030 Claimspriority, application Japan, June 30, 1970,

The portion of the term of the patent subsequent to Dec. 11, 1990, hasbeen disclaimed Int. Cl. C07d 53/06 US. Cl. 260-2393 D 4 Claims ABSTRACTOF THE DISCLOSURE Novel process for preparing l-substituted'benzodiazepine derivatives represented by the formula GET-R2 N-C=O Hwherein R represents hydrogen, halogen, nitro, C C, alkoxy,trifluoromethyl or cyano; R represents hydrogen, C -C allcyl, phenyl oraralkyl; R represents pyridyl or a group of the formula,

R5 (where R, and R are independently hydrogen, halogen, C -C alkyl,trifluoromethyl or cyano); and n represents an integer of 1 to 4, whichcomprises reacting an aminophenylketone derivative represented by theformula,

OH (H) wherein R R and n are the same as defined above, with anoxazolid2,5-dione derivative represented by the formula (III) wherein Ris the same as defined above.

The l-substituted benzodiazepine derivatives represented by the formula(I) have prominent effects as tranquilizer, muscle relaxant,antispasmodic, anticonvulsant and hypnotic.

The present invention relates to a novel process for preparingl-substituted benzodiazepine derivatives. More particularly, the presentinvention pertains to a novel process for preparing benzodiazepinederivatives, and salts thereof, represented by the formula,

R: E=N

R I CH-Rz nHZn OH wherein R represents hydrogen, halogen, nitro, C C,allcoxy, trifluoromethyl or cyano; R represents hydrogen, C -C alkyl,phenyl or aralkyl; R represents pyridyl or a group of the formula,

(where R, and R are independently hydrogen, halogen, C -C alkyl,trifluoromethyl or cyano); and n represents an integer of 1 to 4.

In the compound represented aforesaid formula (I), the C C, alkyl canbe, illustratively, methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyland tertiary butyl groups; the C -C alkoxy includes, for example,methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tertiary butoxygroups; and the halogen includes chlorine, bromine, iodine and fluorine.The group of the formula, C I-I represents a straight chain orbranched-chain alkylene group having up to 4 carbon atoms, and includes,for example, methylene, ethylene, l-methylethylene, 2- methylethylene,trimethylene, l-methyltrimethylene and Z-methyltrimethylene groups.

The l-substituted benzodiazepine derivatives represented by the formula(I) have prominent effects as tranquilizer, muscle relaxant,antispasmodic anticonvulsant and hypnotic, and are of great importanceas medicines.

According to the prior art, the l-substituted benzodiazepin-Z-onederivatives were obtained, for example, by synthesizing1-unsubstituted-1,3-dihydro-2H-1,4-benzodiazepin-Z-one and thenhydroxyalkylating the resultant compound with a hydroxyalkyl halide,preferably after converting the l-unsubstituted compound into a l-sodioderivative thereof. (I. V. Barley et al., J. Med. Chem., 11, 774-777(1968), US. Pat. 3,391,138).

Contrary to this known procedure, we have found, unexpectedly, thatbenzodiazepine derivatives of the formula (I) can be smoothly andeconomically prepared in high yields and of high purity by reacting anaminophenylketone derivative of the formula wherein R is the same asdefined above.

( III) processfor preparing l-subst ituted benzodiazepine derivatives.

Other objects and merits of the present invention will become apparentfrom the description that follows.

In preparing benzodiazepine derivatives according to this invention,aminophenylketone derivatives of the formula (II) are treated with aoxazolid-2,5-dione derivative of the formula (III) in a solvent orsolvent mixture. Suit- ,An object of the present invention is to providea novel able solvent include, for example, chloroform, carbon In mostinstances, the reaction can be conducted at room I temperature or below.Pressure is not necessarily critical and the process can be conducted atatmospheric, subat mospheric or superatmospheric pressure. The process,if desired, can be conducted in an inert atmosphere, such as nitrogen,argon and the like. Although the mole ratio of V the oxazolid-2,5-dionederivative to the aminophenyl kctone derivative is not critical, it ispreferable to use at least stoichiometric amount of the reactant. Inmost cases, it is more preferable to use an excess of the oxazolid 2,5-dione derivative. I

The benzodiazepine derivative obtained according to the above-mentionedprocess may also be isolated in the form of an acid addition salt bytreatment with an acid, e.g. a mineral acid such as hydrochloric,hydrobromic, sulfuric, nitric, or phosphoric acid or an organic acidsuch as maleic, fumaric, succinic, formic or acetic acid.

The present invention is further disclosed in the following Examples ofpreferred embodiments thereof, which are presented for the purpose ofillustration and are not intended to limit the scope of the invention.

EXAMPLE 1 To a solution of 1 g. of Z-(B-hydroxyethyl)amino-5-chlorobenzophenone in 20 ml. of methylene chloride .is added 1.2 g. ofoxazolid-2,5-dione. To the mixture is added 10 ml. of ethereal hydrogenchloride under icecooling, and the mixture is stirred at roomtemperature. The reaction mixture is poured into water, basified withaqueous ammonia and extracted with methylene chloride. The extracts arecombined and dried over sodium sulfate, and the solvent is removed underreduced pressure. The residue is crystallized and recrystallized fromethanol to give l-(B-hydroxyethyl)-5-phenyl-7-chloro 1,3-- dihydro-2H-1,4-benzodiazepin-2-one as colorless prisms, M.P. l58l60 C.

EXAMPLE 2 Using the procedure similar to that described in Example 1,but replacing 2 (fi-hydroxyethyl)amino-S-chlorobenzophenone "by 2(B-hydroxyethyl)amino-5-chloro-2'- fiuorobenzophenone, there is obtained1 (,B-hydroxyethyl)-5-(o-fluorophenyl) -7-chloro 1,3 dihydro 2H 1,4-benzodiazepin-Z-one as a pale yellow viscous oil.

The hydrochloride, obtained in the usual manner with ethereal hydrogenchloride, is recrystallized from methanol-ether to give pale yellowprisms, M.P. 194-196 C. (decomposition).

Similarly, the following compounds are prepared.

l-(fi-Hydroxyethyl)-5-(o-chlorophenyl)-7-chloro-l,3-dihydro-2H-1,4-benzodiazepin-2-one, M.P. 115 116 C.

l-(fl-Hydroxyethyl)-5-phenyl-7nitro-l,3-dihydro-2H-1,4-benzodiazepin-2-one, M.P. 235-236 C.

. '4 -(fi-Hyd oxyethyl)- -phe y -7- r u. o e yl- 1dihydro-2H-1,4-benzodiazepin-2-o ne, M.P. 1 15 116 C.l-(y-Hydroxypropyl)-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one, M.P. 155l56 C.

What is claimed is: I i 1. A process for preparing l-substitutedbenzodiazepine derivatives and acid addition salts thereof representedby the formula,

he... (m

wherein R represents hydrogen, halogen, nitro, C -C alkoxy,trifiuoromethyl or cyano; R represents hydrogen, C -C alkyl, or ,phenyl;R represents pyridyl or a group of the formula,

(where R; and R are independently hydrogen, halogen, C -C alkyltrifluoromethyl or cyano); and n represents an integer of l to 4; whichcomprises reacting an aminophenylketone derivative represented by theformula,

wherein R R and n are the same as defined above, with anoxazolid-2,5-dione derivative represented by the formula,

5 6 diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,References Cited water, methanol, ethanol, dimethylformamide ordimethyl- UMTED STATES PATENTS sulmxlde, mxmrethemf' 3,391,138 7/1968Archer et a1. 260-2393 D 3. A process according to claim 1, wherein theacid is hydrogen chloride, hydrogen bromide, sulfuric acid, phos- 5 JOHND, RANDOLPH, Primary Examiner phoric acid, polyphosphoric acid, borontrifluoride or BOND, Assistant Examiner paratoluenesulfonic acid.

4. A process according to claim 1, wherein the reaction 11.8. C1. X.R.is carried out at a temperature ranging from 0-30 C. 10 260-307 B, 570AB, 296 R, 999

